期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 33, 期 9, 页码 1412-1421出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2013.82
关键词
age-associated; Alzheimer's disease; cerebral amyloid angiopathy; nitric oxide synthase; rapamycin; target-of-rapamycin (TOR); vascular dysfunction
资金
- Ellison Medical Foundation
- William & Ella Owens Medical Research Foundation
- UTHSCSA University Research Council
- UTHSCSA Institute for Integration of Medicine and Science
- NIA Interventions Testing Center [U01AG022307]
- NIH [RC2AG036613]
- NIA [5T32AG021890]
- UTHSCSA
- CTRC at UTHSCSA [NIH-NCI P30 CA54174]
- San Antonio Nathan Shock Aging Center [P30AG-13319]
- Neurodegeneration Research Center (REAP) from the Research and Development Service of the Department of Veterans Affairs
Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h) APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias.
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